This is a long-term research program to develop mild chemical methods for peptide synthesis. These studies are based on the idea of orthogonal protection, particularly by use of the N alpha- dithiasuccinoyl (Dts) amino protecting group and the related class of open-chain carbamoyl disulfides of primary and secondary amines that were developed under this grant. These protecting groups can be rapidly and quantitatively removed under essentially neutral conditions by reduction with thiols and other agents. They are applied for solid-phase peptide synthesis in conjunction with anchoring linkages that are cleavable by mild acid, light, or fluoride ion. A major goal of this grant so far has been the preparation and application of a complete set of orthogonally protected N alpha- Dts amino acid derivatives to the solid-phase synthesis of biologically active peptides. A general method has been developed to cleanly introduce the Dts group onto amino acids, and of the twenty genetically encoded residues, only histidine remains to be appropriately derivatized. Even so, there is a need for further improvements in the preparative conditions with an eye to scale-up for commercial production; promising experiments to achieve this are already underway. Furthermore, studies are planned to settle remaining questions of how to deal with complex residues as asparagine, glutamine, arginine, histidine, cysteine, and tryptophan. Recently published work from this laboratory details protocols for the synthesis of peptides up to a length of ten residues. In every case where Dts-based and other methodologies have been examined side-by-side in a controlled fashion, results with Dts have been demonstrably superior. It remains for the present granting period to demonstrate that substantially longer peptides can be made in significantly better yields and purities than by previous methods.